Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative

Change in cartilage morphometry: a sample of the progressioncohort of the Osteoarthritis Initiative

D J Hunter1,2, J Niu2, Y Zhang2, S Totterman3, J Tamez3, C Dabrowski4, R Davies4, M-PHellio Le Graverand5, M Luchi6, Y Tymofyeyev7, and C R Beals [on behalf of for the OAIInvestigators]71Division of Research, New England Baptist Hospital, Boston, Massachusetts, USA2Boston University School of Medicine at Boston Medical Center, Boston, Massachusetts, USA3VirtualScopics, Rochester, New York, USA4Musculoskeletal Medicines Development Center, GlaxoSmithKline Pharmaceutical Company,Collegeville, Pennsylvania, USA5Pfizer, Global Research and Development, Ann Arbor, Michigan, USA6Novartis, East Hanover, New Jersey, USA7Merck Research Laboratories, Rahway, New Jersey, USA

AbstractObjective—The performance characteristics of hyaline articular cartilage measurement onmagnetic resonance imaging (MRI) need to be accurately delineated before widespread applicationof this technology. Our objective was to assess the rate of natural disease progression of cartilagemorphometry measures from baseline to 1 year in knees with osteoarthritis (OA) from a subset ofparticipants from the Osteoarthritis Initiative (OAI).

Methods—Subjects included for this exploratory analysis are a subset of the approximately 4700participants in the OAI Study. Bilateral radiographs and 3T MRI (Siemans Trio) of the knees andclinical data were obtained at baseline and annually in all participants. 160 subjects from the OAIProgression subcohort all of whom had both frequent symptoms and, in the same knee, radiographicOA based on a screening reading done at the OAI clinics were eligible for this exploratory analysis.One knee from each subject was selected for analysis. 150 participants were included. Using sagittal3D DESSwe (double echo, steady-state sequence with water excitation) MR images from the baselineand 12 follow-up month visit, a segmentation algorithm was applied to the cartilage plates of theindex knee to compute the cartilage volume, normalised cartilage volume (volume normalised tobone surface interface area), and percentage denuded area (total cartilage bone interface area denudedof cartilage).

Results—Summary statistics of the changes (absolute and percentage) from baseline at 1 year andthe standardised response mean (SRM), ie, mean change divided by the SD change were calculated.On average the subjects were 60.9 years of age and obese, with a mean body mass index of 30.3 kg/m2. The SRMs for cartilage volume of various locations are: central medial tibia −0.096; centralmedial femur −0.394; and patella −0.198. The SRMs for normalised cartilage volume of the variouslocations are central medial tibia −0.044, central medial femur −0.338 and patella −0.193. The

Correspondence to: Dr D J Hunter at Division of Research, New England Baptist Hospital, 125 Parker Hill Ave, Boston, MA 02120,USA; [email protected] interests: None.

NIH Public AccessAuthor ManuscriptAnn Rheum Dis. Author manuscript; available in PMC 2009 August 30.

Published in final edited form as:Ann Rheum Dis. 2009 March ; 68(3): 349–356. doi:10.1136/ard.2007.082107.

NIH

-PA Author Manuscript

NIH


NIH


majority of participants had a denuded area at baseline in the central medial femur (62%) and centralmedial tibia (60%). In general, the SRMs were small.

Conclusions—These descriptive results of cartilage morphometry and its change at the 1-year timepoint from the first substantive MRI data release from the OAI Progression subcohort indicate thatthe annualised rates of change are small with the central medial femur showing the greatest consistentchange.

Osteoarthritis (OA) is a significant public health challenge, being ranked as the leading causeof disability in elderly people.1 OA affects an estimated 21 million Americans.2 Recentestimates suggest that symptomatic knee OA occurs in 6% of adults 30 years of age or older,3 and in 13% of people age 60 and over.4

Despite being extraordinarily prevalent OA remains a condition that is poorly understood, anda condition for which available effective therapeutic options are limited to symptomatictreatment. The development of therapies aimed at joint preservation in OA is constrained bythe slow progress of the condition, its heterogeneous clinical manifestations and the need forlong-term follow-up to observe changes in structure.

New technologies may improve the assessment of early disease development, and progression,and could greatly facilitate measurement of structural outcomes in OA clinical trials. Foremostamong these is magnetic resonance imaging (MRI), a sensitive non-invasive method forassessing joint morphology.5 6 MRI is ideally suited for imaging arthritic joints as: (1) it is freeof ionising radiation; (2) it defines both calcified as well as soft tissue joint components; and(3) its tomographic viewing perspective obviates morphological distortion, magnification andsuperimposition. MRI of the knee can directly visualise hyaline articular cartilage and coverthe whole joint in one examination, meaning that the cartilage defects in the joint can bevisualised directly regardless of their location.5

Although yet to be formally accepted by regulatory authorities, many experts now agree thatMRI may be the best imaging technique for monitoring the progression of OA of the knee.5Unfortunately, while MRI has demonstrated great promise, its value in defining disease andas a tool to both monitor disease progression in clinical trials and understand the basis of jointsymptoms is not clear.

Methods of analysing MR images of joints are in their infancy. Depending on the segmentationapproach and the software used, many different morphometric parameters can be measured orderived, including, among others, cartilage volume in pre-defined regions of the knee,thickness, denuded area, and cartilage volume normalised to bone surface area.

There is a significant body of supporting data on the longitudinal change in cartilage volumeas a responsive primary endpoint to reflect OA progression. 5 7–9 It is claimed that MRI offersa more sensitive measure of OA and its progression than x-ray. However, based on recentanalyses the short-term responsiveness of MRI-derived parameters may not be as good as wehad hoped.10 The change of cartilage volume in previous longitudinal studies has varieddramatically but typically shown about 5% loss of knee cartilage volume per year (range ofabout −1 to −8%) in knees with OA.5 These studies were largely done at 1.5T and there maybe performance advantages at 3T given a higher signal and contrast to noise11 and a highertest–retest precision of cartilage measures than 1.5T MRI.12 The performance characteristicsof hyaline articular cartilage measurement on MRI need to be accurately delineated to ensurethat widespread application of this technology in clinical trials is warranted and scientificallyvalid. Advances in the use of MRI for clinical trials of OA depend upon continued investigationof the measurement of each feature in the joint that is imaged, and assessment of the metricproperties of these measures.

Hunter et al. Page 2

Ann Rheum Dis. Author manuscript; available in PMC 2009 August 30.

NIH


NIH


NIH


The objective of this exploratory analysis is to assess the rate of natural disease progression ofcartilage morphometry measures from baseline to 1 year in knees with OA from a subset ofparticipants from the OAI Progression subcohort.

MATERIALS AND METHODSStudy sample

Subjects included for this exploratory analysis are a subset of the 4796 participants participatingin the OAI Study, which is an ongoing 4-year, multi-centre, longitudinal, prospectiveobservational cohort study, focusing primarily on knee OA. The study protocol, amendments,and informed consent documentation were reviewed and approved by the local institutionalreview boards. Data used in the preparation of this article were obtained from the OsteoarthritisInitiative (OAI) database, which is available for public access at http://www.oai.ucsf.edu/. Thespecific data sets used are clinical data set 0.1.1 and Image Release 0.B.1 and 1.B.1.

As the study is observational in nature, no blinding procedure is required and no specifichypothesis is predefined.

OAI consists of two subcohorts: progression subcohort and an incidence subcohort. Twodifferent populations of subjects were recruited; 1389 patients with radiographic signs andsymptoms of knee OA at baseline were recruited into the progression subcohort and anothergroup at risk for symptomatic knee OA was recruited to the incidence subcohort. All of theparticipants for the present study are drawn from the progression subcohort.

The inclusion criteria for the progression subcohort of the OAI required that both of thefollowing criteria must be present together in at least one knee at baseline:

1. Frequent knee symptoms, defined as pain, aching or stiffness on most days of a monthduring the past year, AND

2. Radiographic evidence of OA defined as definite tibiofemoral osteophytes (OARSIatlas grade ≥1) on x-ray. Subjects with severe narrowing (OARSI grade 3 narrowingor bone on bone) in both knees were planned to be excluded. The grading ofosteophytes and joint space narrowing was done at each individual OAI enrolmentcentre.

A total of 160 subjects from the OAI progression subcohort were included in this exploratoryanalysis. These were selected by OAI from participants who had complete baseline and 1 yearMRI data in early 2006, with blocking for sex and centre. This is a convenience sample ofsubjects.

Radiographic assessmentThe bilateral posteroanterior views were obtained using a SynaFlexer frame (Synarc, Inc., SanFrancisco, California, USA) to position the subject’s feet reproducibly. Body weight isdistributed equally between the two legs and the knees and thighs are pressed directly againstthe wall of the frame, the anterior wall of which was in contact with the Bucky or recliningtabletop of the radiographic unit. This positioning results in a fixed angle of knee flexion ofabout 20°. A V-shaped angulation support on the base of the frame is used to fix the foot belowthe index knee in 10° external rotation. The x-ray beam is angled 10° caudal.13

Baseline and follow-up radiographs of the sample of 160 subjects were read independently bytwo study readers, one a bone and joint radiologist, and the other a rheumatologist (DH). Kneex-rays were read in a paired fashion, blinded to sequence. Readers evaluated the Kellgren andLawrence (K&L) grade on a 0–4 scale14 as well as individual radiographic features, ie,



NIH


NIH


NIH


http://www.oai.ucsf.edu/

osteophytes and joint space narrowing on a 0–3 scale of each knee at both time points usingthe OARSI atlas.15 For the K&L grade we used adjudicated readings that were arrived at by aconsensus of the readers. Disagreements on joint space narrowing were also adjudicated if thetwo readers disagreed.

DH also assessed the anatomical axis and minimum joint space width at the time of thesereadings. Digital imaging software (eFilm Workstation (Version 2.0.0) software) was used tocompose reference lines and calculate these measures. The anatomical axis was defined as theangle formed by the intersection of two lines originating from points bisecting the femur andtibia and converging at the centre of the tibial spine tips consistent with the methods describedby Kraus et al where varus is negative.16 The origin of these lines was 10 cm from the kneejoint surfaces when included in the field of view on the radiograph.

Selection of knee for analysisBilateral MRIs from 160 participants were provided by OAI but only one knee from 150patients (one knee per subject) was identified for analysis. The rationale for the reducing thesample from 160 to 150 was that the budget for processing the images was limited and inaddition we wanted to optimise the use of subjects more likely to progress. The selection ofthe index knee for this analysis was based on the presence of both symptoms (frequent kneepain) and radiographic evidence of OA in the same knee (see appendix for further details—see web only file).

Magnetic resonance imaging sequence parametersImages were acquired on a 3T MRI scanner (Siemens Magnetom Trio, Erlangen, Germany)and a quadrature transmit- receive knee coil (USA Instruments, Aurora, Ohio, USA). For thepurposes of cartilage segmentation we used the sagittal 3D DESSwe (double echo, steady-statesequence with water excitation) images with a slice thickness of 0.7 mm, 16.3 ms repetitiontime, 4.7 ms time to echo, 25° flip angle, 160 slices, 140 mm field of view; 384×307 matrix;in-plane resolution 0.37 mm×0.46 mm (interpolated to an isotropic in-plane resolution of 0.37mm×0.37 mm), 185 Hz/pixel bandwidth, 0% phase oversampling, 10% slice oversampling,80% phase resolution, 100% slice resolution, 1 average, elliptical filter on, asymmetric echooff, anterior/posterior phase encoding, fast gradient and fast radiofrequency options(acquisition time 10 min 23 s).

Magnetic resonance imaging postprocessingThe analysis of the DESS sequences was done using a semiautomated segmentations algorithmdescribed in detail in the appendix. Image pairs were blinded to time point (baseline or 1 year).

After image segmentation, the following measures were analysed:

1. Cartilage volume

2. Normalised cartilage volume (volume normalised to bone surface interface area). Thebone surface interface area is the area of the cartilage in contact with bone. Thenormalisation was done by dividing the measured cartilage volume by the area ofmeasured cartilage in contact with bone plus the area of full-thickness defects(denuded area of bone).

3. Denuded area (total cartilage bone interface area denuded of cartilage). The denudedarea is the area of bone where a full-thickness cartilage defect is present.



NIH


NIH


NIH


Statistical analysisThe objective of this analysis was to assess, in subjects with knee OA, the rate of naturalprogression of the disease as measured by the change or percentage change from baseline to 1year in the regular (non-normalised) cartilage volume, normalised cartilage volume anddenuded surface area within regions of the knee. Owing to patients being observed at variablefollow-up times at 1 year, changes from baseline were annualised assuming a linear trend overtime. Image pairs were randomised in a 1:1 ratio using a block randomisation scheme to twodifferent paired analysis scenarios: baseline supervised segmentation follow by trackedsegmentation of the 1-year follow-up (denoted by work-flow A) or 1-year supervisedsegmentation followed by a tracked segmentation of the baseline MRI (denoted by work-flowB). Owing to the bias associated with supervised versus tracked segmentation, subjects fromwork-flow A group have thickness and volume annual decreases underestimated by bias bi andsubjects from work-flow B have annual decreases overestimated by bias bi, where i denotesMRI parameter i.

To estimate the bias associated with work flow, a statistical model for the annual change wasdeveloped with work flow as a factor. For each affected endpoint, the magnitude of bias, bi,was estimated and used to obtain corrected (unbiased) measurements of change from baseline.These corrections were applied to each patient, and they rely on the reasonable assumption thatthe randomisation was effective.

From the bias-corrected data set, summary statistics of the changes (absolute and percentage)from baseline at 1 year and the standardised response mean (SRM), ie, mean change dividedby the SD change were calculated. The denuded area parameters were not normally distributedwith a large number of values at both baseline and year 1 equal to zero.

A trimming algorithm that removes cartilage tissue outside of a 1 mm thick boundary regionwas used to reduce the variability in the definition of cartilage tissue. This strategy wasgenerally successful because the variability of most cartilage measures was reduced aftertrimming (data not shown). The trimmed results are presented for each cartilage morphometrybiomarker. The baseline values, annualised mean change and annualised percentage changeare each displayed. We also present the changes for two subpopulations of patients. Patientswith intermediate OA (K&L grade 2 or 3) and those with definitive OA and varus alignmentwere separately analysed as these populations may be more likely to experience progression.The definition of varus alignment was defined as subjects with anatomic axis more varus than−2°. There was an extreme positive outlier in change of patella cartilage volume, which madethe variance of change large, which has been removed for the patella assessments.

All statistics were computed using SAS 9.0. In accordance with the data user agreement of theOAI the patient level quantitative morphology results in this analysis will be made availablethrough the OAI website.

RESULTSThe demographic characteristics of the study sample are displayed in table 1. On average thesubjects were 60.9 years of age and obese with a mean body mass index of 30.3 kg/m2.Approximately half (51%) of the study sample were female, as designed in the OAI protocol.Sixteen per cent of the study sample did not have radiographic OA using the commonlyaccepted criteria of K&L grade ≥2. This circumstance arose because eligibility into the OAIprogression subcohort was based on the identification of a definite tibiofemoral osteophyte bythe individual OAI enrolment centre and some disagreement in radiographic assessment withthe adjudicated scoring is expected.



NIH


NIH


NIH


The rate of natural progression of the disease as measured by the change in the regular (non-normalised) cartilage volume, normalised cartilage volume, and denuded surface area over aperiod of 1 year within regions of the knee are depicted in table 2–table 4. The results forcartilage volume and normalised cartilage volume are presented in table 2 and table 3. Forexample, the baseline and mean change in cartilage volume for the central medial femur are1504.12 mm and −37.44 mm3 respectively, which gives an SRM of −0.394 or a percentagechange of −2.46%. In the subsample (n = 116) of knees with K&L grade 2 or 3, the meanchange is −33.94 mm3 and in those from the subsample (n = 59) in knees with K&L 2–4 andvarus angulation, the mean change was −34.93 mm3. The SRMs vary across the differentlocations in the knee; however, in general they are small. The SRMs for cartilage volume ofvarious locations are central medial tibia −0.096, central medial femur −0.394 and patella−0.198 (where a negative sign indicates cartilage loss). In general the SRMs for normalisedcartilage volume are slightly less than those for cartilage volume. The SRMs for normalisedcartilage volume of the various locations are central medial tibia −0.044, central medial femur−0.338 and patella −0.193. In general, the results for the subsample analyses for participantsat higher risk for progression are similar to the whole sample. The distribution of change incartilage volume and normalised cartilage volume for the central medial femur is shown in fig1 and fig 2.

The results for the denuded surface area are presented in table 4, with a positive valuerepresenting increasing denuded area. The majority of participants had a denuded area atbaseline in the central medial femur (62%) (fig 3) and central medial tibia (60%). Again thecentral medial femur demonstrated more change than the other cartilage plates with an SRMof 0.239.

DISCUSSIONThe OAI is a longitudinal cohort study that has among its aims to assess the validity of MRI-derived morphology biomarkers for OA disease progression. We used state-of-the-art analysismethods to analyse numerous morphological biomarkers in articular cartilage from MRI. Thispaper presents descriptive results of cartilage morphometry and its change at the 1-year timepoint from the first substantive MRI data release from the OAI progression subcohort. Ingeneral, the annualised rates of change are small with the central medial femur showing thegreatest consistent change.

The longitudinal change from the participants in this study is smaller than the majority of valuespublished in previous longitudinal studies, which typically demonstrated about 5% loss of kneecartilage volume per year (range of about −1 to −8%) in knees with OA5 This then raisesquestions regarding differences between the study protocols or analysis technologies, whichmay explain very different rates of progression. The methods in previous studies differmarkedly from those described here, including that they use a completely manual method oftracing boundaries for segmentation, analysis is read unblinded to time point order, haveacquired images using 1.5T scanners and a different pulse sequence to that used here. However,our results are consistent with recent data from other studies using similar cartilagequantification techniques that showed cartilage volume loss of about −1 to −3% per year(including MAK,17 Pfizer18 and more recently data by Eckstein et al from OAI).19 These morerecent studies have generally found rates of loss similar to what we have found in the medialtibia and femoral plates. If these more recent estimates of cartilage volume change areconfirmed, then there are important implications for future clinical trials of disease-modifyingtreatments for OA using MRI techniques.

While significance tests are frequently used to assess change they do not indicate the magnitudeof change. To give greater meaning to the amount of change the concept of responsiveness was



NIH


NIH


NIH


introduced. The term responsiveness is used as an indicator of sensitivity to change. There aremany responsiveness indicators that result in different effect size indices. Most of theseindicators agree on the numerator (change from baseline to follow-up); however, there is littleagreement on the appropriate denominator. Effect sizes greater than 0.2 are generally held tobe clinically detectable.20 Cohen20 came up with conventions for these values that constitutea ‘‘trivial’’ (ES <0.20), small (ES ≥0.20 <0.50), medium (ES ≥0.50 <0.80), and a large effect(ES ≥0.80). There is more controversy over the interpretation of other indices ofresponsiveness, including SRMs; however, if we were to generalise, the SRMs in this analysisare trivial to small.

The percentage change is calculated as change divided by baseline measure, so change andpercentage change always have the same sign for each individual. However, their means in thepopulation may not necessarily have the same sign. When the mean of change was calculated,each subject’s change was weighted with 1/sample size and summarised. However, when themean of percentage change was calculated, each subject’s change was weighted with 1/(baseline measure×sample size) and summarised.

Several structure modification studies have based their sample size estimates on MRI-basedrates of volume change of about 5% with an SD of 5% per year in knee cartilage volume.Projected sample size depends on: (1) the expected rate of progression in participants treatedwith placebo; (2) the minimum magnitude of the drug effect, or rate of progression expectedin the active treatment arm(s); (3) the variation in progression rate that occurs betweenparticipants; and (4) the precision of the measurement technique. In a simple analysis of changefrom baseline, to detect a 50% reduction in loss of baseline cartilage volume over 1 year requiresevaluable data on 64 participants per arm if the expected background progression is 5% (SD5%), but 250 per arm if it is 5% (SD 10%) (for 80% power, a (two-sided) 0.05).9 A modestwithin-subject correlation of ρ = 0.7 would reduce the sample size by a factor of 2.3. However,change on the order of 1% (SD 10%) as observed in this study would require a prohibitivelylarge sample size (N~6400/arm) until the correlation reaches values on the order of 0.99. Ifthese estimates of cartilage change are confirmed, then for MRI to be a useful tool with whichto study OA progression then it will be necessary to develop more sensitive algorithms to detectstructural change in the joint, and identify study populations undergoing more rapid diseaseprogression.

How can we explain that the cartilage volume of some regions remains the same while thedenuded areas appear to be increasing? Cartilage volume and thickness changes aggregateareas of cartilage swelling with separate areas experiencing a reduction in thickness, reducingthe ability of these summary measures to identify change. In early OA, cartilage may not bethin but instead is thicker and swollen with water, which is imbibed by cartilage when thecollagen network is disrupted and the role of proteoglycans is altered.21 22 Increasing thicknessmay also reflect a healthy trophic response to focal loading for normal cartilage as distinct fromearly disease. Thus measuring cartilage volume or mean thickness in regions of the knee (eg,medial tibia) and regional mean thickness may provide a very different measure of importantpathological change when compared with focal measures of change centred around focaldefects in diseased joints.23 Further, these measures cannot assess the composition of cartilagethat can be measured using MRI techniques to ascertain alteration in proteoglycan and collagencontent that may accompany swelling of cartilage.24 Distinguishing the MRI measures that arethe most sensitive to change and are correlated with clinical symptoms is essential if we are toutilise them appropriately. Future work with this data set will investigate the association ofMRI morphology measures with clinical symptoms. Moreover, we plan to estimate thecartilage loss involving partial and complete thickness focal cartilage defects.



NIH


NIH


NIH


As seen in previous studies, the variability in femoral cartilage volume measures (especiallythe posterior femoral condyles) is greater than other knee compartments potentially reflectingdifficulties with lack of contrast among tissues in this region or due to partial volume effectsin this curved surface.

This study has several limitations. The MRI postprocessing technique used every other sliceas opposed to every slice. We anticipate a slight improvement in precision if each slice is usedin the analysis. Another potential limitation is that we quantified cartilage morphometry usingthe DESSwe sequence rather than the more standard FLASH sequence, although the formerhas been cross-validated with the latter.25 The automated, pairwise image segmentation processwe used imposes a bias on cartilage thickness and volume measurements, and is a uniquefeature of our methodology. Paired image analysis is typically more precise than unpairedimage analysis, and biases imposed by these processes need to be presented and accounted forin analysis. The relative advantages of our analysis methods will require independentsegmentation and quantification of these images by alternative image analysis techniques.

The separation of the cartilage tissue into several compartments introduces noise into the regionof interest measurements. Without this subdivision it is impossible to report localised changesin the central femur, and the analysis, therefore, the ability to detect changes will be minimised.On the other hand, the segmentation of cartilage plates was done using an automated processthat only increases marginally the measurement error.

The original description of the K&L grade was made and developed on weight bearing, fullyextended films not on films that were semi-flexed such as in this study.

The sample used in this analysis had a smaller cartilage change than reported in otherpopulations. One likely explanation is that cartilage change is greater in subjects with moreadvanced OA. 24 of 150 (16%) of our sample were participants with K&L grade 0 and 1,effectively a population without definitive radiographic OA (but with persistent knee pain). Inother studies the greatest change in cartilage morphology has been seen in those with K&Lgrade 3 disease. Further, the sample in this study is heterogeneous with respect to whether themedial or lateral compartment is primarily involved in OA. Mediolateral frontal knee alignmenthas been shown to be a significant risk factor for disease progression in the primarily loadedtibiofemoral knee compartment.26 We plan to conduct further studies of this population andevaluate whether enriching the sample for certain features that predict progression such asmeniscal damage, bone marrow lesion and alignment will facilitate identification of a cohortof persons at risk for greater progression.

In summary, the rates of change of cartilage morphometry in people with knee OA in this studyare small. These results need to be replicated and published by other investigators using otherimage analysis tools and software algorithms. Our results should stimulate discussion as towhich MRI parameters should be measured in longitudinal studies of OA progression and howbest to perform these measurements. The greater complexity and cost of MRI joint morphologywill need to prove its value.

Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.

AcknowledgementsWe would like to thank the Principal Investigators (Michael Nevitt, Kent Kwoh, Charles B. Eaton, Rebecca Jackson,Marc Hochberg, Joan Bathon), Co-investigators and staff of the Osteoarthritis Initiative. I would also like toacknowledge the following persons who contributed to this work: Piran Aliabadi (read the knee x-ray films) and David



NIH


NIH


NIH


Felson (chaired the x-ray adjudication sessions). Would like to acknowledge the input of Merck statisticians YevgenTymofyeyev and Amy Ko, David Raunig from Pfizer, and Randall Smith from GSK.

Funding: The OAI is a public–private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259;N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of theDepartment of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partnersinclude Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc.Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health.

The Osteoarthritis Initiative and this pilot study are conducted and supported by the National Institute of Arthritis andMusculoskeletal and Skin Diseases (N01-AR-2-2262, N01-AR-2-2262, N01-AR-2-2258) in collaboration with theOAI Investigators and Consultants. This manuscript has been reviewed by the OAI Publication committee for scientificcontent and data interpretation.

REFERENCES1. Prevalence of disabilities and associated health conditions among adults—United States 1999. MMWR

Morb Mortal Wkly Rep 2001;50:120–125. [PubMed: 11393491][erratum appears in MMWR MorbMortal Wkly Rep 2001;50:149.].

2. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of theprevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum1998;41:778–799. [PubMed: 9588729][see comments.].

3. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, et al. Osteoarthritis: newinsights. Part 1: the disease and its risk factors. Ann Intern Med 2000;133:635–646. [PubMed:11033593][Review] [120 refs].

4. Dunlop DD, Manheim LM, Song J, Chang RW. Arthritis prevalence and activity limitations in olderadults. Arthritis Rheum 2001;44:212–221. [PubMed: 11212163]

5. Eckstein F, Glaser C. Measuring cartilage morphology with quantitative magnetic resonance imaging.Semin Musculoskeletal Radiol 2004;8:329–353.[Review] [150 refs].

6. Peterfy CG, Guermazi A, Zaim S, Tirman PF, Miaux Y, White D, et al. Whole-Organ MagneticResonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage2004;12:177–190. [PubMed: 14972335]

7. Graichen H, Eisenhart-Rothe R, Vogl T, Englmeier K, Eckstein F. Quantitative assessment of cartilagestatus in osteoarthritis with qMRI—validation study in total knee arthroplasty beyond cartilagevolume. Arthritis Rheum 2004;50:811–816. [PubMed: 15022323]

8. Cicuttini FM, Wluka AE, Stuckey SL. Tibial and femoral cartilage changes in knee osteoarthritis. AnnRheum Dis 2001;60:977–980. [PubMed: 11557657]

9. Wluka AE, Stuckey S, Snaddon J, Cicuttini FM. The determinants of change in tibial cartilage volumein osteoarthritic knees. Arthritis Rheum 2002;46:2065–2072. [PubMed: 12209510]

10. Hunter D, Conaghan P, Peterfy C, Bloch D, Guermazi A, Woodworth T, et al. Responsiveness, effectsize, and smallest detectable difference of magnetic resonance imaging in knee osteoarthritis.Osteoarthritis Cartilage 2006;14:112–115.

11. Kornaat PR, Reeder SB, Koo S, Brittain JH, Yu H, Andriacchi TP, et al. MR imaging of articularcartilage at 1.5T and 3.0T: comparison of SPGR and SSFP sequences. Osteoarthritis Cartilage2005;13:338–344. [PubMed: 15780647]

12. Eckstein F, Charles HC, Buck RJ, Kraus VB, Remmers AE, Hudelmaier M, et al. Accuracy andprecision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.Arthritis Rheum 2005;52:3132–3136. [PubMed: 16200592]

13. Peterfy C, Li J, Zaim S, Duryea J, Lynch J, Miaux Y, et al. Comparison of fixed-flexion positioningwith fluoroscopic semi-flexed positioning for quantifying radiographic joint-space width in the knee:test-retest reproducibility. Skeletal Radiol 2003;32:128–132. [PubMed: 12605275]

14. Kellgren, JH.; Lawrence, JS. Atlas of standard radiographs. Oxford: Blackwell Scientific; 1963.15. Altman RD, Hochberg M, Murphy WAJ, Wolfe F, Lequesne M. Atlas of individual radiographic

features in osteoarthritis. Osteoarthritis Cartilage 1995;3:3–70. [PubMed: 8581752]



NIH


NIH


NIH


16. Kraus VB, Vail TP, Worrell T, McDaniel G, Kraus VB, Vail TP, et al. A comparative assessment ofalignment angle of the knee by radiographic and physical examination methods. Arthritis Rheum2005;52:1730–1735. [PubMed: 15934069]

17. Eckstein F, Wirth W, Hudelmaier M, Stein V, Lengfelder V, Cahue S, et al. Patterns of femorotibialcartilage loss in knees with neutral, varus, and valgus alignment. Arthritis Rheum 2008;59:156–170.

18. Hellio Le Graverand MP, Wyman B, Buck R, Wirth W, Hudelmaier M, Eckstein F. Twelve monthlongitudinal change in regional cartilage morphology in a multicenter, multivendor MRI study at 3.0Tesla—The A9001140 Study [abstract]. Arthritis Rheum 2007;56:S282.

19. Eckstein F, Maschek S, Wirth W, Wyman B, Hudelmaier M, Nevitt M, et al. Change in femorotibialcartilage volume and subregional cartilage thickness over 1 year-data from the OsteoarthritisInitiative Progression Subcohort [abstract]. Arthritis Rheum 2007;56:S283.

20. Cohen, J. Statistical power analysis for the behavioral sciences. New York: Academic Press; 1977.21. Maroudas A, Bullough P. Permeability of articular cartilage. Nature 1968;219:1260–1261. [PubMed:

5677422]22. Mow, V.; Setton, L. Mechanical properties of normal and osteoarthritis articular cartilage. In: Brandt,

K.; Doherty, M.; Lohmander, LS., editors. Osteoarthritis. New York: Oxford Medical Publications;1998. p. 108-122.

23. Graichen H, Al Shamari D, Hinterwimmer S, Eisenhart-Rothe R, Vogl T, Eckstein F, et al. Accuracyof quantitative magnetic resonance imaging in the detection of ex vivo focal cartilage defects. AnnRheum Dis 2005;64:1120–1125. [PubMed: 15640266]

24. Gray ML, Burstein D. Molecular (and functional) imaging of articular cartilage. J MusculoskeletalNeuronal Interactions 2004;4:365–368.[Review] [69 refs].

25. Eckstein F, Hudelmaier M, Wirth W, Kiefer B, Jackson R, Yu J, et al. Double echo steady statemagnetic resonance imaging of knee articular cartilage at 3 Tesla: a pilot study for the OsteoarthritisInitiative. Ann Rheum Dis 2006;65:433–441. [PubMed: 16126797]

26. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment indisease progression and functional decline in knee osteoarthritis. JAMA 2001;286:188–195.[PubMed: 11448282][erratum appears in JAMA 2001;286:792.].

27. Tamez-Pena J, Barbu-McInnis M, Lerner A, Totterman S. Unsupervised definition of the tibia-femoral joint regions of the human knee and its applications to cartilage analysis [abstract]. SPIE:Medical Imaging. 2006

28. Tamez-Pena J, Barbu-McInnis M, Totterman S. Knee cartilage extraction and bone-cartilage interfaceanalysis from 3D MRI data sets [abstract]. Proceedings of SPIE, Medical Imaging. 2004



NIH


NIH


NIH


Figure 1.Change in cartilage volume (VC) of central medial femur (cMF)–cumulative distributionfunction (CDF).



NIH


NIH


NIH


Figure 2.Change in normalised cartilage volume (VC) of central medial femur (cMF)–cumulativedistribution function (CDF).



NIH


NIH


NIH


Figure 3.Denuded area of central medial femur at baseline cumulative distribution function (CDF).



NIH


NIH


NIH


NIH


NIH


NIH



Table 1Descriptive characteristics of study sample (n = 150)

Gender (female N (%)) 76 (51)

Age (mean, SD) years 60.9 (9.9)

Age group (<65 years N (%)) 91 (61)

Body mass index, kg/m2, mean (SD) 30.3 (4.7)

Interval between visit, days

mean (SD) 391.1 (35.4)

median 385.3

range 335–546

Index knee (left N (%)) 73 (49)

Kellgren and Lawrence grade of index knee, no. (%)

Grade 0 6 (4)

Grade 1 18 (12)

Grade 2 56 (37)

Grade 3 60 (40)

Grade 4 10 (7)

Knee and hip surgery, including arthroscopy (yes forstudy knee N (%))

45 (30)

History of knee injury (yes for study knee N (%)) ever injuredbadly enough to limit ability to walk for at least 2 days

71 (47.3)


NIH


NIH


NIH


Hunter et al. Page 15Ta

ble

2C

artil

age

volu

me

trim

med

(mm

3 ): b

asel

ine

valu

e, a

nnua

lised

mea

n (S

D) c

hang

e an

d SR

M fo

r thi

s cha

nge,

ann

ualis

ed p

erce

ntag

e (S

D)

chan

ge (n

= 1

50)

Loc

atio

nB

asel

ine

mea

n (S

D)

Mea

n ch

ange

(SD

)fr

om m

odel

SRM

for

mea

n ch

ange

% c

hang

e (S

D)

Mea

n ch

ange

inkn

ees w

ith K

&L

= 2

or 3

(SD

) n =

116

Mea

n ch

ange

inkn

ees w

ith K

&L

= 2–

4 an

d va

rus

angu

latio

n (S

D)

n =

59

Fem

ur11

861

.38

(321

9.41

)−3

8.04

(363

.00)

−0.1

05−0

.26

(2.9

7)−3

8.75

(322

.70)

−39.

47 (3

62.0

0)

Lat T

ibia

2256

.25

(731

.27)

−20.

96 (8

6.19

)−0

.243

−0.8

0 (3

.75)

−21.

74 (7

7.86

)−1

6.76

(80.

69)

Med

Tib

ia19

88.9

6 (6

44.3

2)−4

.38

(106

.63)

−0.0

410.

03 (5

.03)

5.23

(101

.03)

−3.3

8 (1

04.5

5)

Pate

lla26

73.7

8 (1

210.

23)

−25.

32 (1

34.3

1)−0

.189

−1.0

9 (8

.06)

−27.

70 (1

35.5

8)−1

5.0

(137

.90)

Troc

hlea

4523

.57

(147

6.50

)−1

.12

(190

.00)

−0.0

06−0

.08

(4.4

5)−1

.14

(172

.36)

12.8

6 (1

91.9

8)

Cen

t Lat

Fem

ur17

36.7

6 (5

58.1

8)−3

.38

(58.

80)

−0.0

57−0

.25

(3.3

6)−5

.41

(58.

10)

−11.

46 (6

7.58

)

Cen

t Lat

Tib

ia18

80.0

0 (6

06.8

0)−1

4.89

(68.

50)

−0.2

17−0

.84

(4.2

3)−1

7.69

(68.

37)

−12.

69 (6

4.72

)

Cen

t Med

Fem

ur15

04.1

2 (7

01.5

2)−3

7.44

(94.

92)

−0.3

94−2

.46

(12.

29)

−33.

94 (8

1.42

)−3

4.93

(95.

17)

Cen

t Med

Tib

ia13

17.7

6 (5

08.7

3)−7

.96

(83.

13)

−0.0

96−0

.20

(7.1

1)1.

78 (8

4.00

)−6

.62

(84.

15)

Post

Lat

Fem

ur16

40.0

(562

.49)

12.0

9 (9

3.37

) 0

.129

0.9

2 (5

.50)

11.6

4 (9

1.57

)11

.08

(80.

84)

Post

Med

Fem

ur17

29.8

1 (4

95.9

9)−3

.81

(74.

94)

−0.0

51 0

.08

(4.6

2)−8

.41

(72.

16)

−7.4

4 (7

0.89

)

Cen

t+Po

st M

ed F

emur

3233

.93

(109

6.68

)−4

0.84

(132

.37)

−0.3

09−1

.09

(4.4

5)−4

2.34

(118

.20)

−42.

36 (1

28.7

0)

Cen

t+Po

stM

edFe

mur

+Med

Tibi

a52

21.8

9 (1

665.

00)

−45.

35 (1

97.8

1)−0

.229

−0.7

0 (3

.88)

−37.

11 (1

76.0

3)−4

5.74

(194

.38)

Cen

t, ce

ntra

l; K

&L,

Kel

lgre

n an

d La

wre

nce

(gra

de);

Lat,

late

ral;

Med

, med

ial;

Post

, pos

terio

r; SR

M, s

tand

ardi

sed

resp

onse

mea

n.


NIH


NIH


NIH



ble

3N

orm

alis

ed ca

rtila

ge v

olum

e trim

med

(mm

): ba

selin

e val

ue, a

nnua

lised

mea

n (S

D) c

hang

e, an

nual

ised

per

cent

age (

SD) c

hang

e (n

= 15

0)

Loc

atio

nB

asel

ine

mea

n (S

D)

Mea

n ch

ange

(SD

)fr

om m

odel

SRM

for

mea

n ch

ange

% c

hang

e (S

D)

Mea

n ch

ange

inkn

ees w

ith K

&L

= 2

or 3

(SD

) n =

116

Mea

n ch

ange

inkn

ees w

ith K

&L

= 2–

4 an

d va

rus

angu

latio

n (S

D)

n =

59

Fem

ur2.

34 (0

.37)

−0.0

054

(0.0

58)

−0.0

93−0

.23

(2.8

7)−0

.008

2 (0

.062

)−0

.003

4 (0

.071

)

Lat T

ibia

2.27

(0.4

3)−0

.017

(0.0

63)

−0.2

69−0

.75

(4.0

9)−0

.019

(0.0

87)

−0.0

18 (0

.090

)

Med

Tib

ia1.

81 (0

.38)

−0.0

014

(0.0

79)

−0.0

17 0

.14

(5.1

6) 0

.008

6 (0

.092

)−0

.000

88 (0

.094

)

Pate

lla2.

27 (0

.80)

−0.0

18 (0

.11)

−0.1

62−0

.92

(7.9

2)−0

.024

(0.1

1)−0

.006

0 (0

.107

)

Troc

hlea

2.30

(0.5

5)−0

.001

3 (0

.073

)−0

.018

−0.2

0 (4

.27)

−0.0

066

(0.0

83)

0.0

092

(0.0

94)

Cen

t Lat

Fem

ur2.

25 (0

.41)

−0.0

090

(0.0

71)

−0.1

26−0

.39

(3.5

8)−0

.009

4 (0

.079

)−0

.009

5 (0

.082

)

Cen

t Lat

Tib

ia2.

36 (0

.51)

−0.0

15 (0

.071

)−0

.215

−0.6

6 (4

.28)

−0.0

17 (0

.093

)−0

.016

(0.0

91)

Cen

t Med

Fem

ur1.

88 (0

.69)

−0.0

39 (0

.12)

−0.3

38−1

.92

(12.

22)

−0.0

35 (0

.11)

−0.0

40 (0

.12)

Cen

t Med

Tib

ia1.

76 (0

.46)

−0.0

043

(0.0

98)

−0.0

44−0

.20

(6.8

7) 0

.005

7 (0

.11)

−0.0

048

(0.1

1)

Post

Lat

Fem

ur2.

61 (0

.41)

0.0

28 (0

.13)

0.2

23 1

.15

(5.4

6) 0

.024

(0.1

4) 0

.034

(0.1

4)

Post

Med

Fem

ur2.

40 (0

.43)

−0.0

069

(0.0

90)

−0.0

76−0

.01

(4.5

0)−0

.013

(0.1

0)−0

.016

(0.1

0)

Cen

t+Po

st M

ed F

emur

4.28

(0.9

8)−0

.046

(0.1

5)−0

.296

−0.8

3 (4

.32)

−0.0

47 (0

.16)

−0.0

56 (0

.17)

Cen

t+Po

stM

edFe

mur

+Med

Tibi

a6.

09 (1

.30)

−0.0

47 (0

.19)

−0.2

44−0

.57

(3.8

7)−0

.039

(0.2

1)−0

.057

(0.2

2)

Cen

t, ce

ntra

l; K

&L,

Kel

lgre

n an

d La

wre

nce

(gra

de);

Lat,

late

ral;

Med

, med

ial;

Post

, pos

terio

r; SR

M, s

tand

ardi

sed

resp

onse

mea

n.


NIH


NIH


NIH



ble

4D

enud

ed su

rfac

e ar

eas (

mm

2 ) tr

imm

ed: b

asel

ine

valu

e, a

nnua

lised

mea

n (S

D) c

hang

e, a

nnua

lised

per

cent

age

(SD

) cha

nge

(n =

150

)

Loc

atio

nB

asel

ine

mea

n (S

D)

No.

(%) o

fpa

rtic

ipan

ts w

ithde

nude

d ar

ea a

tba

selin

e

Mea

n ch

ange

(SD

)fr

om m

odel

SRM

Mea

n ch

ange

inkn

ees w

ith K

&L

= 2

or 3

(SD

) n =

116

Mea

n ch

ange

inkn

ees w

ith K

&L

= 2–

4 an

d va

rus

angu

latio

n (S

D)

n =

59

Fem

ur17

6.64

(241

.21)

124

(82.

7) 8

.97

(37.

26)

0.24

117

.58

(48.

80)

8.3

8 (5

8.75

)

Lat T

ibia

6.91

(28.

06)

55 (3

6.7)

0.9

6 (9

.22)

0.10

4 0

.63

(11.

73)

−0.4

8 (6

.21)

Med

Tib

ia44

.16

(109

.13)

69 (4

6.0)

2.0

6 (2

1.62

)0.

095

2.3

8 (1

7.72

) 3

.44

(21.

34)

Pate

lla97

.71

(208

.50)

81 (5

4.0)

−1.6

4 (3

0.47

)−0

.054

−0.6

0 (3

5.10

)−3

.54

(28.

18)

Troc

hlea

99.0

7 (1

98.4

3)89

(59.

3) 1

.14

(23.

48)

0.04

9 9

.88

(41.

67)

−0.2

5 (4

6.49

)

Cen

t Lat

Fem

ur4.

03 (1

8.15

)84

(56.

0) 0

.65

(5.4

8)0.

118

0.7

7 (6

.12)

0.6

3 (2

.55)

Cen

t Lat

Tib

ia4.

57 (2

4.51

)89

(59.

3) 0

.76

(8.9

3)0.

085

0.7

8 (1

0.68

)−0

.86

(4.9

7)

Cen

t Med

Fem

ur60

.88

(128

.69)

93 (6

2.0)

6.4

7 (2

7.08

)0.

239

6.6

4 (2

2.24

) 8

.35

(33.

63)

Cen

t Med

Tib

ia43

.28

(107

.76)

90 (6

0.0)

1.7

9 (1

9.36

)0.

092

2.1

7 (1

6.93

) 3

.13

(20.

80)

Post

Lat

Fem

ur1.

00 (6

.19)

7 (4

.7)

0.3

7 (2

.82)

0.13

1 0

.41

(2.7

6) 0

.037

(0.1

2)

Post

Med

Fem

ur8.

76 (3

5.49

)84

(56.

0) 0

.16

(10.

69)

0.01

5 0

.15

(9.9

1)−0

.15

(13.

85)

Cen

t+Po

st M

ed F

emur

69.6

4 (1

47.7

4)94

(62.

7) 6

.63

(30.

88)

0.21

5 6

.79

(26.

87)

8.2

0 (3

8.07

)

Cen

t+Po

stM

edFe

mur

+Med

Tibi

a11

3.81

(248

.61)

109

(72.

7) 8

.69

(42.

65)

0.20

4 9

.17

(37.

50)

11.6

4 (4

9.58

)

Cen

t, ce

ntra

l; K

&L,

Kel

lgre

n an

d La

wre

nce (

grad

e); L

at, l

ater

al; M

ed, m

edia

l; Po

st, p

oste

rior;

SRM

, sta

ndar

dise

d re

spon

se m

ean.

Per

cent

age o

f cha

nge o

n de

nude

d su

rfac

e are

as w

as n

ot d

efin

ed b

ecau

seso

me

knee

s had

zer

o ba

selin

e va

lues

and

non

-zer

o fo

llow

-up

valu

es.


Date post:	16-May-2023
Category:	Documents
Upload:	independent
View:	0 times
Download:	0 times

Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative

Documents